Our laboratory has completed one of the first comprehensive evaluations of the presence of NADPH oxidase family members in human tumors. We found that NADPH oxidase 5 (NOX 5)is found in melanomas and in hematologic malingancies;dual oxidase 2 is found in various gastrointestinal malignancies. We have expressed both of these human proteins in melanoma and pancreatic tumor cell model systems to understand their functions in vitro. NOX 5 overexpression has been found to downregulate p27, alter cell cycle progression, and generate considerable amounts of extracellular hydrogen peroxide after exposure to ionomycin. Duox 2 overexpression has been found to also lead to altered cell cycle progression, a remarkable degree of extracellular reactive oxygen metabolism, to be inducible with interferon gamma which functions, in part, by demethylating the duox 2 promoter. Both of these genes may play an important role in producing an oxidant "bystander" effect. Our overall goal is to understand the function of these oxidases in human cancer, which, to date has not been explored in detail.